The development of small molecule sensors for the selective detection and imaging of proteins and certain cell types has great implications for biomedical and basic research. In particular, small molecule fluorophores have received significant attention as sensors in flow cytometry and fluorescence microscopy. Identification of small molecule fluorophores able to selectively discriminate one protein from a complex mixture is a challenge in this field. Similarly, the development of a sensor capable of selectively staining certain cell types is highly desirable in cell-imaging research.
BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) has been widely used as a fluorophore due to its high photostability and extinction coefficient, high quantum yield and narrow excitation/emission bandwidth.1-3 In order to develop fluorescent sensors and probes,4-7 several chemical reactions have been adapted to the BODIPY scaffold. Mono- and difunctionalized BODIPY derivatives can be prepared by solution-phase chemistry using nucleophilic and oxidative nucleophilic hydrogen substitutions,8-10 Knoevenagel condensations,11,12 Liebeskind-Srogl reactions,13,14 and palladium-catalyzed couplings15-18 amongst others. However, solution-phase syntheses of BODIPY dyes often encompass tedious purification steps with typically low recovery yields. This limitation may have little impact on the synthesis of individual compounds, but it seriously hampers the combinatorial derivatization of the BODIPY scaffold,19-21 requiring labor intensive purification processes. Solid-phase methodologies have been successfully applied to the diversification of fluorescent scaffolds that involve challenging purification steps, but the adaptability of the BODIPY structure to solid-phase chemistry has been questioned due to its lability under both basic and acidic conditions.22 
Due to the current limitations associated with solid-phase synthesis of BODIPY scaffolds, and due to their potential to operate as selective sensors in protein and cell detection and imaging, it is highly desirable to develop a combinatorial solid-phase synthesis of the BODIPY scaffold.